Title:Design of SGLT2 Inhibitors for the Treatment of Type 2 Diabetes: A History Driven by Biology to Chemistry
Volume: 11
Issue: 4
Author(s): Wenqing Cai, Linlin Jiang, Yafei Xie, Yuqiang Liu, Wei Liu and Guilong Zhao
Affiliation:
Keywords:
Drug design, C-glycoside, SGLT2 inhibitor, structure-activity relationship (SAR), type 2 diabetes.
Abstract: A brief history of the design of sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors
is reviewed. The design of O-glucoside SGLT2 inhibitors by structural modification of phlorizin, a
naturally occurring O-glucoside, in the early stage was a process mainly driven by biology with anticipation
of improving SGLT2/SGLT1 selectivity and increasing metabolic stability. Discovery of dapagliflozin,
a pioneering C-glucoside SGLT2 inhibitor developed by Bristol-Myers Squibb, represents an
important milestone in this history. In the second stage, the design of C-glycoside SGLT2 inhibitors by
modifications of the aglycone and glucose moiety of dapagliflozin, an original structural template for almost all C-glycoside
SGLT2 inhibitors, was mainly driven by synthetic organic chemistry due to the challenge of designing dapagliflozin
derivatives that are patentable, biologically active and synthetically accessible. Structure-activity relationships
(SAR) of the SGLT2 inhibitors are also discussed.